Since the discovery of the vasoactive effects of glyceryl trinitrate (also referred to as nitroglycerin), compounds containing nitrate or nitrite esters groups have been used in the treatment of various cardiovascular disorders such as, angina pectoris, congestive heart failure and myocardial infarction. See Parratt, J. R., J. Pharm. Pharmacol., 31, 801 (1979). The utility of these compounds arises from their ability to release nitric oxide (NO). See Ignarro, L. J., Pharmaceutical Research 6, 651 (1989). NO is believed to activate a soluble form of guanylate cyclase, a cellular enzyme, which catalyses the formation of 3',5' cyclic guanosine monophosphate (cGMP). See Kamm, et al., Annu. Rev. Physiol., 51, 299 (1989). It is the action of cGMP on other cellular targets that is thought to mediate relaxation of vascular smooth muscle and provide the therapeutic effect of nitrovasodilators.
A problem with the use of nitrovasodilators is their tendency to produce "tolerance." See Katz, R. J., Cardiovascular Drugs and therapy, 4, 247 (1990). Ignarro, L. J., et al., (J. Pharmacol. Exp. Ther., 218, 739 (1981)) have suggested this tolerance effect results from depletion of intracellular sulfhydrals, such as glutathione, which are essential in the metabolism of nitrovasodilators to NO.
Tolerance of N-acetyl-3-(nitrosothio)-D-valine, also known as S-nitroso-N-acetylpenicillamine (SNAP), is much less of a problem than tolerance of gyceryl trinitrate, and SNAP is one of the most stable nitrosothiols known (see Field, L., et al., J.C.S. Chem. Commun., 249(1978)). SNAP would be an especially useful drug if it could be delivered in such manner as vasodilating organic nitrates and nitrites currently in clinical use, i.e., orally (including sublingually), rectally, vaginally, nasally or transdermally. However, it is poorly absorbed by these routes.
It has now been found that certain novel ester derivatives of SNAP i.e., the compounds of the present invention, are active as low tolerance producing vasodilators, and are much better absorbed through the skin and mucous membranes than SNAP itself. Therefore, these derivatives are suited for oral, rectal, vaginal, nasal and transdermal applications. Some of the compounds of this invention are more potent vasodilators than SNAP and are comparable in this activity to gyceryl trinitrate.